Third Keystone Symposium on Cellular Immunology and the Immunotherapy of Cancer Antigen Processing and Presentation Chimpanzee Dendritic Cells Derived In Vitro from Blood Monocytes and Pulsed with Antigen Elicit Specific Immune Responses In Vivo

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Abstract

Dendritic cells differentiated in vitro from blood and other sources using cytokines hold particular promise as immunothcrapeulic agents in cancer. However, there are currently no data to show that human in vitro-derived dendritic cells are immunogenic in vivo. We have developed a primate model of immunotherapy using dendritic cells differentiated in vitro from blood monocytes by culturing with human granulocyte/ macrophage colony-stimulating factor and interieukin-4. We measured the immune response to antigen elicited by in vitro-derived and antigen-treated dendritic cells following a single intravenous inoculation and boost in chimpanzees. The antigens tested were ovalbumin, a complex foreign protein, and a peptide derived from the MUC-1 mucin tumor antigen, a relatively uncomplex self antigen. Four chimpanzees were immunized either with antigen-pulsed dendritic cells (two animals) or mock-treated dendritic cells (one animal) given intravenously or both antigens given in adjuvant subcutaneously (one animal). Each animal received a boost of both antigens in adjuvant 10 days later. All animals responded with an IgG-mediated humoral response to ovalbumin measured in the serum at day 24. This was associated with a proliferative cellular response to ovalbumin in the inguinal lymph node draining the boost injection. In contrast, antibody responses to mucin peptide were detected in one animal in response to the boost injection, and no T cell proliferative responses to mucin peptide were detected in the draining lymph node of any animal. To determine if the single inoculation of antigen-pulsed dendritic cells elicited any immunity, we measured the T cell response to ovalbumin in blood monoouclear cells harvested prior to the boost Ovalbumin-specific proliferative responses that were antigen dose dependent were detected in one of two treated animals. In contrast, ovalbumin given with adjuvant and mock-treated dendritic cells induced no response. The three animals inoculated with dendritic cells, either antigen or mock treated, had moderate T cell responses to bovine serum albumin, a constituent of the medium used to culture cells prior to injection. We conclude from these data that in vitro-derived dendritic cells can elicit T cell responses to a complex foreign antigen following a single intravenous injection in a large primate, ft is likely that immunity to a simple self antigen, MUC-1 mucin peptide, may require multiple inoculations. The results support the use of dendritic cells differentiated in vitro as vehicles for immunotherapy in humans.

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